ABSTRACT Schistosomiasis, caused by a parasitic flatworm, is a disease of poverty infecting over 200 million people with 800 million at risk. Treatment and control of this disease relies on just one drug, praziquantel (PZQ) ? a precarious situation should drug resistance emerge. Also, the therapeutic profile of PZQ is not ideal. Accordingly, the World Health Organization has declared schistosomiasis a disease for which new therapies are urgently needed. Currently, drug discovery for helminths like schistosomes relies on phenotypic (whole-organism) screens of cultured parasites. However, these screens in isolation are not fully comprehensive and do not indicate why and how worms die, i.e., either the molecular targets engaged during response to a drug, or the mechanisms of drug action (MoA) - information that is important for advancing new drugs to the clinic. The availability of high quality genomic resources for the schistosome parasite is opening up new opportunities for drug and drug target research and development. Leveraging, therefore, the well-annotated gene models of the reference Schistosoma mansoni genome, our first Aim is to employ gene expression profiling (GEP) via RNA-sequencing (RNA- Seq) to understand how the parasite responds to drug insult at the whole transcriptome (mRNA) level. Because of ongoing drug discovery efforts by the PI, we have a number of high-value chemistries supplied by pharmaceutical industry to test. These include chemically very similar compounds that induce different phenotypic responses in the parasite suggesting that different targets and/or MoAs are engaged. RNA-Seq and advanced bioinformatics support will help resolve the shared and compound-specific gene expression changes associated with dying worms at a system-wide level. For our second Aim, we will use the signature expression patterns observed in the RNA-Seq data, to identify schistosome biomarker genes that, when incorporated into a molecular (qPCR) screen, will predict drug lethality, provide insight on MoA for the chosen drug sets and aid drug development activities to maintain focus on the desired chemical structures. Our Aims are supported by a substantial drug development program for schistosomiasis by the PI that includes access to privileged small molecule chemistries and a unique high-content phenotypic screen platform to measure the drug- induced responses of the parasite. The goals of the project, expertise of the PI in drug discovery and skills of the co- Investigator in genomics and next-generation sequencing provide a unifying systems biology perspective into how this parasite responds to drug insult. The strategies and tools developed will provide a template for exploration of drug- induced gene perturbations in other medically important parasites.